INTRODUCTION The larynx is the most
common site of head and neck cancer (HNC) in the United States . In
data from the American Cancer Society, larynx cancer accounted for
31 percent of the 30,990 cases of HNC diagnosed annually . The
male-to-female ratio of 4 to 5:1 is, at least in part, reflective of
differences in tobacco and alcohol use.

The larynx is divided into three
anatomic regions: the supraglottic region larynx, glottic larynx
(true vocal cords and mucosa of the anterior and posterior
commissures), and the subglottic larynx which extends to the
inferior border of the cricoid cartilage

Laryngeal cancers are often
discovered at an earlier stage than other head and neck cancers,
because hoarseness tends to occur relatively early in the course of
the disease. However, the symptoms associated with cancer of the
larynx, particularly hoarseness, depend upon location. Persistent
hoarseness is frequently the initial complaint in glottic cancers;
later symptoms may include dysphagia, referred otalgia, chronic
cough, hemoptysis, and stridor. Supraglottic cancers are often
discovered later and may present with airway obstruction or palpable
metastatic lymph nodes; hoarseness is an uncommon presenting sign.
Primary subglottic tumors are rare, and affected patients typically
present with stridor or complaints of dyspnea on exertion.

Biologic behavior also varies
according to location .
Supraglottic cancers are richly supplied with lymphatics, leading to
a high frequency of cervical nodal metastases. The lymphatic
drainage of the right and left sides of the supraglottic larynx and
subglottic larynx and those structures below it are separate; this
knowledge allows prediction of metastatic behavior and also affects
planning of larynx conservation operations. In comparison, the true
vocal cords (glottic larynx) possess little or no lymphatic
drainage.

Given the fundamental role that the
larynx plays in human speech and communication, determining the
optimal management of laryngeal cancer must consider both survival
and the functional consequences of the given treatment approach.
Total laryngectomy is widely recognized as one of the surgical
procedures most feared by patients. Although different options for
voice rehabilitations exist, many patients express dissatisfaction
with the results, and social isolation, job loss, and depression are
common sequelae. (

As a result, much effort has focused
on larynx-sparing approaches, such as radiation therapy (RT) alone,
combined chemotherapy and RT, and function-preserving partial
laryngectomy procedures. Treatment guidelines for laryngeal cancer
from the American Society of Clinical Oncology, published in 2006,
recommend that all patients
with T1 or T2 larynx cancer be treated, at least initially, with
intent to preserve the larynx

TREATMENT OF EARLY STAGE LARYNGEAL CANCER By definition,
patients with stage I and II disease have no evidence of nodal
involvement. Specific management of the neck in patients with head
and neck cancer and a clinically negative neck examination,
including the role for neck dissection, is discussed separately.

RT
versus surgery For patients with early stage (T1-2N0)
disease, both RT and surgery have the potential to cure a high
proportion of patients. There are no randomized trials in which RT
has been compared to surgery (laryngectomy or conservation surgery)
for treatment of early stage disease. Similarly, there are no
randomized data comparing functional outcomes (ie, voice quality and
swallowing ability) after surgery or RT for this stage of disease.
Treatment recommendations are largely based upon evidence from
prospective uncontrolled studies and retrospective cohort series.

In general, because
overall outcomes from
surgery and RT appear to be similar for early stage disease, the
choice of therapy is often dictated by preservation of voice, which
favors RT. However, RT may result in other complications that
can adversely affect quality of life (QOL). Furthermore, local tumor recurrence after
RT may be amenable to salvage by organ preserving surgery, but total
laryngectomy will be necessary for a substantial proportion of such
patients, particularly those with T2 tumors.

Another challenge is that limited
stage disease represents a wide spectrum of disease, and multiple
factors (eg, tumor location, volume, extent of invasion into the
vocal cord, involvement of the anterior commissure, nodal
metastases, patient age, occupation, compliance, and preference)
need to be considered in choosing therapy. These issues can be
illustrated by the following examples :

For well-defined favorable T1 glottic cancers (ie,
superficial tumors located in the middle third of the cord,
particularly on its free edge), endoscopic laser resection can
result in a good voice outcome, and is preferred over RT, which
takes longer to administer. On the other hand, lesions that are
indistinct, particularly those arising in the context of
widespread, abnormal-appearing mucosa, are more suitable for RT
than surgery.

RT is preferred by many clinicians for treatment of T2
glottic cancers that have preserved vocal cord mobility and are
characterized as superficial on radiographic imaging. Local
control rates are high and functional outcomes are good.
However, survival may be compromised after failure of RT in such
patients , leading some to recommend supracricoid partial
laryngectomy with cricohyoidoepiglottopexy for patients who are
willing to sacrifice some voice quality in an effort to improve
local control.

Combined
modality therapy Single-modality treatment is effective for
limited stage, invasive cancer of the larynx. Treatment guidelines
from ASCO emphasize that every effort should be made to avoid
combining surgery with RT because functional outcomes may be
compromised. If undertaken, larynx-preserving surgical excision of
the primary tumor should aim to achieve tumor-free margins.
Narrow-margin excision followed by postoperative RT is not an
acceptable treatment approach.

Induction chemotherapy has been
investigated as a treatment for early stage larynx cancer . However,
in contrast to the situation with locoregionally advanced disease,
the data are insufficient to recommend this approach outside of the
context of a clinical trial.
Concurrent chemoradiotherapy may be used as an option for larynx
preservation, even if a partial laryngectomy would be possible.

Tobacco
abuseContinued
cigarette smoking is associated with a worse outcome after RT.
Patients should be encouraged to abstain from smoking after
diagnosis, throughout treatment, and thereafter.

The following section will address
the choice of treatment according to the subsite of disease.

Supraglottis Lesions of the supraglottic larynx tend to
spread locally and metastasize frequently to the cervical nodes. The
supraglottis is considered a midline structure; as a result, there
is a substantial incidence (15 percent or greater) of bilateral
cervical nodal metastasis . The net effect is that many patients
with a clinically negative neck have occult (histologically)
positive cervical nodes, and there is a high frequency of relapse
and eventual death in patients who do not undergo elective treatment
of the neck.

Guidelines from ASCO recommend that
all patients with
supraglottic cancer should have elective neck treatment, even if
clinically N0 . We recommend selective neck dissection or RT
for the clinically negative neck, and a neck dissection with or
without RT for palpable lymphadenopathy.

Early supraglottic cancers can be
effectively treated with a voice-preserving supraglottic
laryngectomy or RT, as long as both sides of the neck are also
treated. In a retrospective review of 166 consecutive patients with
T1-T2 carcinoma of the supraglottic larynx treated between the years
1983 and 1992 , 66 patients underwent conservative surgery and 100
underwent definitive RT. Overall five-year survival for the entire
group was 72 percent. Survival for patients in the surgical group
was 88.4 percent, whereas for the RT group it was 76.4 percent.
Ninety-five percent of patients in the surgery group and 72 percent
in the RT group had laryngeal preservation. Selection bias could
have affected these outcomes.

Surgery
Early stage primary disease is highly curable by laryngeal surgery,
preferably using procedures that remove only the upper portion of
the larynx. This supraglottic laryngectomy is physiologic and
permits retention of vocal and swallowing functions.
Contraindications to supraglottic laryngectomy include impairment of
vocal cord mobility or extension to the true vocal cord,
interarytenoid area, piriform sinus apex, post-cricoid region or
thyroid cartilage. Resection for tumors that have extended to one
arytenoid, tongue base, or medial wall of piriform sinus constitutes
"extended" supraglottic laryngectomy. These are still considered
conservation surgeries, but require a longer period of swallowing
rehabilitation.

Some aspiration is expected
postoperatively; therefore, poor pulmonary function is also a
contraindication to supraglottic laryngectomy. There are no clearly
accepted ways to measure adequate pulmonary function. Some surgeons
rely on clinical assessment of a patient's activities (walking,
stair climbing), while others rely upon formal pulmonary function
testing. An FEV1/FVC less than 50 percent may signify a greater risk
of severe aspiration complications

Local control and survival rates for
supraglottic laryngectomy are excellent for early stage disease . In
one series of 104 patients in which 29 percent of the patients
received supraglottic laryngectomy and the remainder total
laryngectomy, the five-year survival was 100 percent for T1 and 81
percent for T2 disease .

Endoscopic
laser resection Several studies have evaluated the use of
endoscopic laser resection of early stage supraglottic cancer . This
procedure can result in high cure rates if clear surgical margins
can be obtained. In a study of 70 patients with cancer of the
supraglottic larynx, five-year recurrence-free survival was 85
percent for stage I, and 63 percent for stage II cancers . However,
the procedure is not without risk. This was illustrated by a second
study of 46 patients with T1/2 cancers of the supraglottic larynx,
treated with intraoral laser ablation . The calculated overall
survival was 59 percent after five years; among the eight patients
who died with disease, four had uncontrollable local or regional
recurrences and five (11 percent) failed to relearn swallowing,
requiring total laryngectomy.

The criteria for patient selection
remain to be established, although most authors agree that early
stage suprahyoid lesions are most amenable to endoscopic treatment.
Treatment of the clinically negative neck should be strongly
considered.

RadiotherapyExcellent local control has
been achieved for cancers of the supraglottic larynx after external
beam (EBRT), approximating 90 percent for T1 lesions and 80 to 89
percent for T2 lesions . Five-year survival in patients
treated with EBRT are comparable to the results obtained with
primary surgery. As an example, in one study of 166 patients with
T1-2N0 cancers of the supraglottic larynx, 66 underwent conservative
surgery and 100 had definitive RT . The following outcomes were
noted:

The five-year overall survival was 72 percent.

The five-year disease-free survival with conservative
surgery and RT was 88 and 76 percent, respectively.

Laryngeal preservation was successful in the majority of
patients (82 percent overall, 95 percent with conservative
surgery, and 72 percent with RT).

Fifty percent of local recurrences after RT could be
salvaged with laryngectomy.

Because of the complications
associated with persistent swelling and swallowing difficulty,
partial laryngectomy is not recommended for patients who have failed
RT. The salvage procedure in such patients is a total laryngectomy.

The
initial treatment volume for EBRT includes the larynx and
subdigastric, midjugular, and low jugular nodes, and uses opposed
lateral upper fields matched with a single anterior lower field. The
inferior border of the upper fields should be placed at the bottom
of the cricoid cartilage or at least 2 cm below the inferior extent
of disease when there is subglottic extension. A small cord block
should be placed at the superior border of the lower field to avoid
overlap of portals.

The outcome from EBRT may be enhanced
by maneuvers such as accelerated treatment plans (eg,
hyperfractionation) , and the use of radiation sensitizers . In one
study of hyperfractionation, RT doses of 67.2 to 72 Gy were
administered in 1.6 Gy fractions twice daily over six weeks in 169
patients with cancer of the supraglottic larynx . Local control
rates were 96 percent for T1 and 86 percent for T2 disease, and the
corresponding relapse-free survival rates were 78 and 82 percent at
a median follow-up of 56 months. Including surgical salvage, the
ultimate local control rates were 96 and 93 percent, respectively.
The voice preservation rate was somewhat higher in patients with T1
tumors (96 versus 80 percent with T2 tumors).

Management
of the neckIn
contrast to patients with supraglottic cancers, those with early
stage (T1-2) glottic cancers and a clinically negative neck do not
require elective treatment of the neck nodes . However, patients
with advanced (T3-4) lesions of the glottis should have elective
treatment of the neck, even if clinically N0.

Recommendation
We recommend RT as the treatment of choice for T1 lesions and
nonbulky, exophytic T2 lesions. Patients who are medically unfit to
undergo a voice-preserving supraglottic laryngectomy (eg, inadequate
pulmonary function) should also be treated with definitive RT. For
patients with T2 N+ disease, concurrent chemoradiotherapy is an
appropriate choice for larynx preservation (see below).

Glottis
Glottic or true vocal cord cancer is the most common of all
laryngeal cancers in the United States. Most true vocal cord cancers
occur on the anterior two-thirds of the cords and a small percentage
develop on the anterior commissure.

Although
both RT and conservation surgery result in similar rates of survival
and local control, patients with early glottic carcinomas usually
undergo RT due to superior voice results. Vocal quality
following RT is not normal, but is near normal in most patients. In
comparison, all patients are hoarse to a variable degree following
hemilaryngectomy. Patients who undergo
laser excision of T1 cancers may be hoarse post-operatively,
depending on the site of the lesion on the vocal cord. Most patients
are hoarse to a variable degree following hemilaryngectomy for
larger T1 or T2 cancers

These issues were illustrated in a
retrospective study that reviewed outcomes of 551 patients treated
with conservative surgery or RT for glottic carcinoma. For early
stage carcinomas (88 percent of cases), there were no significant
differences in five-year survival among patients treated with
endoscopic laser resection, VPL or RT. However, there were two
advantages to conservative surgery: a lower local tumor recurrence
rate (12 versus 27 percent) and a higher voice preservation rate (83
versus 72 percent), but not necessarily improved quality of speech.

For these reasons,
RT is usually recommended
for T1 lesions and for T2 lesions in which there is no impairment of
vocal cord mobility . The more bulky T2 lesions, particularly
those associated with impairment of motion, are better treated with
voice-preserving hemilaryngectomy, particularly if the patient is
obese and is at risk for radiation "geographic miss" . Another mode
of therapy receiving increasing attention is endoscopic laser
resection, but this procedure is more difficult in these patients
because of close proximity to the underlying cartilage .

The necessity for elective neck
dissection remains somewhat controversial in glottic carcinomas.
Early lesions have a low
incidence of occult nodal disease because the vocal cords possess
little or no lymphatic drainage . One study, for example,
retrospectively reviewed the course of 92 patients who had either
undergone neck dissection or been observed for a minimum of two
years after primary treatment . The incidence of occult nodal
disease was 0 and 19 percent in early and late stage disease,
respectively. For this reason, expectant management with observation
of the neck is acceptable as long as the patient is reliable for
frequent follow-up .

Surgery
The surgical procedure most often used for patients with early
glottic cancer is vertical partial laryngectomy (VPL). In this
procedure, the surgeon bisects the larynx and removes a portion or
all of the true and false vocal cord along with the ipsilateral half
of the thyroid cartilage. Reconstruction can be completed with strap
muscles or cervical fascia. This procedure results in acceptable
five-year survival rates (90 to 95 percent for T1 and 85 percent for
T2), but can be complicated by suboptimal voice quality and the need
for salvage laryngectomy due to local recurrence in 2 to 15 percent
of patients. If the carcinoma is bulky or associated with impaired
mobility, the surgeon may elect to dissect the ipsilateral neck.

Supracricoid partial laryngectomy
with cricohyoidoepiglottopexy (SCPL-CHP) is another approach that
has been advocated to control selected advanced supraglottic/transglottic
tumors classified as T3-T4 for which the conventional surgical
alternative would have been total or near-total laryngectomy . The
avoidance of a permanent stoma for respiration and the continuity of
laryngeal phonation following surgery are significant advantages. (See
"Speech and swallowing rehabilitation of the patient with head and
neck cancer"). For the majority of
patients, these advantages greatly outweigh the temporary but
occasionally severe dysphagia during the acute post-operative
period, and permanent alterations in vocal quality associated with
the procedure. These procedures require adequate pulmonary reserve
because of the temporary aspiration that usually occurs following
surgery.

Endoscopic
laser resection For appropriate patients, endoscopic laser
resection of early glottic cancers allows simultaneous biopsy,
staging, and definitive treatment. Earlier studies included only T1
lesions that did not extend to the anterior commissure,
periarytenoid, or subglottic areas, while more recent studies
include T1b lesions (cross anterior commissure) as well as some T2
lesions (extend to sub- or supraglottis by definition) that are
treated with narrow margin laser resection . When less than one-half
of the cordal depth is resected, two-thirds of the working
thyroarytenoid muscle remains, allowing for a functional voice.
Local tumor control and voice quality appear to be acceptable when
laser therapy is used for T1 lesions of the vocal cord, as
illustrated by the following data:

In the largest series, 151 patients with T1 or Tis
glottic carcinoma underwent CO2 laser cordectomy, the three-year
local control rates for Tis, T1a, and T1b tumors were 100, 94,
and 91 percent, respective .

The success of salvage therapy for local recurrence was
illustrated in a report in which 40 of 48 patients with Tis or
T1 glottic lesions were treated with endoscopic resection; four
had disease persistence despite multiple procedures, and four
recurred locally. All eight were successfully salvaged with RT,
hemilaryngectomy, or total laryngectomy; the four-year disease
control rate was 100 percent, with a laryngeal preservation rate
of 96 percent.

Although randomized trials are not
available, laser therapy seems to result in similar local control,
laryngeal preservation, and survival as RT or surgery . One study
compared 31 patients with T1N0M0 glottic carcinoma undergoing laser
microsurgery with 41 who underwent RT, and 34 who had partial
laryngectomy . The five and ten year rates of locoregional control
and overall survival were 91 and 87 percent, and 78 and 62 percent,
respectively, and did not differ by procedure. There was a trend
toward partial laryngectomy being associated with a worse
satisfaction, and more hoarseness and breathiness than either
radiotherapy or laser microsurgery.

RadiationLocal control is achieved
with RT in approximately 90 percent of patients with T1 lesions and
70 to 80 percent of those with T2 lesions . In one study of 519 such
patients, five-year local control rates were 94, 93, 80, and 72
percent in patients with T1A, T1B, T2A (T2 lesion with normal vocal
cord mobility), and T2B (T2 lesion with impaired vocal cord
mobility) disease, respectively.

Several studies have evaluated the
effect of RT dose, treatment duration, and fraction size on tumor
control.

There appears to be a significant dose-response curve for RT
in T1 glottic cancer. There is a significantly lower probability
of local tumor control at total doses below 61 to 65 Gy .

A shorter total duration of RT appears to improve outcome.
In one series of 398 consecutive patients with early glottic
cancer, the five-year local control rate for T2 lesions treated
within 43 days versus longer than 43 days was 100 and 84
percent, respectively. Overall treatment duration was not a
significant factor influencing outcome for T1 lesions in this
study, but a second series suggested that the
probability of five-year
local control for T1N0 glottic cancer decreased from 95 to 79
percent for treatment time of 22 to 29 days versus 40 days or
longer.

Increasing the dose administered per fraction may also
improve local control . In one report, the five-year rate of
local control for T2 lesions was higher at fraction sizes 2.25
Gy compared to <1.8 Gy (84 versus 44 percent) .

The benefit of accelerated fractionation RT is unclear. In
one retrospective series of 85 patients, hyperfractionated RT
(1.72 Gy per fraction, two fractions per day, 5 days per week,
total 55 or 58 Gy) did not appear to improve local control
probability when compared to conventional fractionation (5 daily
2 Gy fractions per week for a total of 64 Gy). The five-year
local control probability for T1 tumors with accelerated and
conventional fractionation was 87 and 80 percent, respectively,
while for T2 tumors, it was 75 and 73 percent, respectively.

In contrast, a second retrospective
report of 240 patients did suggest a benefit for hyperfractionation
(twice daily to a total 74 to 80 Gy) as compared to once daily
therapy (at doses ranging from 32 to 75 Gy) . The five-year local
control rates were 79 and 67 percent, respectively. However,
interpretation of this study is compromised by the range of doses
used for single daily therapy, and the selection of patients for
daily treatment who were considered poor candidates for twice daily
treatment.

RT to the glottic larynx is usually
administered using opposed lateral, wedged, low energy photons (5 x
5 cm or 6 x 6 cm field sizes). Some institutions advocate blocking
the arytenoids after 50 Gy in order to reduce the severity of
arytenoid edema; the advantage of this approach, however, is
uncertain . Based upon the apparent importance of RT dose and
duration, we use 66 Gy/33 fractions for T1 lesions and 70 Gy/35
fractions for T2 lesions.

Local recurrence, which occurs in 13
to 24 percent of radiated patients, usually is managed by salvage
surgery. Conservative surgery (VPL or subtotal laryngectomy with
cricohyoidopexy) can be used in selected cases to preserve laryngeal
function .

The prognosis for local control in
glottic cancers also appears to be influenced by factors unrelated
to treatment. Poor
prognostic factors include anterior commissure involvement,
particularly in T1 lesions ; subglottic extension in T2 lesions ;
bulky tumors (defined as the presence of visible rather than
subclinical disease) ; and a low pretreatment hemoglobin
concentration .

Recommendation
We recommend laser resection of T1 carcinomas that are localized to
the vocal cord, without extension to the arytenoid or anterior
commissure. We usually recommend RT for other T1 lesions, and
vertical hemilaryngectomy for appropriate patients with T2 lesions
of the larynx. These patients, like those with supraglottic cancers,
require adequate pulmonary reserve for successful swallowing and
vocal rehabilitation. We usually recommend RT for those with
inadequate pulmonary reserve.

Management
of T3N0 glottic carcinoma The best therapeutic approach
for T3N0 tumors of the glottis is uncertain. Although these patients
may be considered for chemoradiotherapy approaches as for those with
locoregionally advanced disease (see below), selected patients may
do well with conservation surgery with or without neoadjuvant
chemotherapy [7]
or RT alone.

One series reviewed outcomes in 200
patients with T3N0 glottic cancer who were treated by a variety of
approaches, including total laryngectomy with or without RT,
conservation surgery with and without RT, or RT alone [64]
. At five years, the disease-specific and overall survival rates
were 67 and 54 percent respectively, and did not differ according to
treatment modality. Locoregional control and laryngeal preservation
was achieved in 74 and 70 percent, respectively, and also did not
vary according to treatment.

Subglottis The subglottic region of the larynx is defined as
the cylindrical area bordered inferiorly by the lower margin of the
cricoid cartilage and by an imaginary circle 5 mm below the free
margin of the true vocal cords. Tumors in this region can be either
primary or secondary due to subglottic extension from some other
site, usually the glottis. Primary malignant lesions of the
subglottis are rare; in one review of 2201 patients diagnosed with
laryngeal cancer over a 33-year period at one institution, only 1.8
percent had primary lesions of the subglottis .

Subglottic tumors are usually
asymptomatic but can present with hoarseness, dyspnea, or stridor.
Direct extralaryngeal extension is common, and the disease is often
advanced at presentation . For these reasons, survival figures are
lower than those observed at other laryngeal subsites. As an
example, in the study described above, 19 patients with T1 or T2
subglottic cancer were treated with total laryngectomy, RT, or
combination therapy. Overall and disease-free five-year survival was
86 and 71 percent for T1 and 50 and 42 percent for T2 disease.

In contrast to lesions
involving the supraglottic larynx and true glottis, total
laryngectomy and appropriate neck surgery, including thyroidectomy,
followed by RT is usually recommended. Prophylactic neck
dissection has not been shown to improve survival.

For patients who desire
laryngeal conservation, primary RT followed by surgical salvage may
be considered, although no study has directly compared this approach
to upfront surgery followed by RT, and it is not clear how this
compares to primary surgery . If this approach is utilized,
chemotherapy should probably be added, at least for T3/4 tumors,
based upon data from glottic and supraglottic cancers.

Summary
and ASCO guidelines The available evidence supports the
use of larynx preservation approaches for the treatment of patients
with early stage (T1 or 2) invasive laryngeal cancer. However, no
larynx preservation approach offers a survival advantage over total
laryngectomy and adjuvant therapy. Treatment guidelines for
laryngeal cancer from the American Society of Clinical Oncology,
published in 2006, recommend that all patients with T1 or T2 larynx
cancer be treated, at least initially, with intent to preserve the
larynx

TREATMENT OF LOCOREGIONALLY ADVANCED DISEASE
Locoregionally advanced squamous cell carcinoma of the larynx
represents a difficult management problem. Long-term survival rates
range from 20 to 60 percent, depending upon the site, stage, and
resectability of the tumor. Traditional therapy for patients whose
cancers are resectable has generally consisted of surgery followed
by adjuvant RT or RT alone. However, these approaches have potential
limitations:

One would like to minimize the extent of surgery without
sacrificing survival

RT may be compromised by factors such as repopulation of
tumor cells, tumor hypoxia, and resistance to radiation

Organ-sparing approaches Because of these limitations,
organ sparing approaches, most of which incorporate chemotherapy,
have been evaluated in patients with locoregionally advanced
laryngeal cancer. Neoadjuvant or induction chemotherapy, followed by
RT permits larynx preservation in a high percentage of such
patients, but does not improve survival compared to radiation alone,
and in the seminal US Intergroup 91-11 study , the rates of larynx
preservation were lower than achieved by concomitant
chemoradiotherapy. Induction chemotherapy will not be discussed
further here, and is presented in detail elsewhere. (See
"Organ preservation in locoregionally advanced laryngeal and
hypopharyngeal cancer: Neoadjuvant chemotherapy").

Concomitant chemoradiotherapy (CRT)
combines RT with chemotherapy in an attempt to take advantage of
synergistic effects and provide early eradication of micrometastases.
Randomized studies of CRT in patients with unresectable disease have
demonstrated survival that is similar to what would be expected in
locoregionally advanced, resectable disease. For this reason, a
number of studies have been conducted utilizing CRT as a substitute
for surgery in patients with otherwise resectable laryngeal cancer,
with the major goal of organ preservation. Although there are no
controlled data concerning the effect of these regimens on survival
compared to surgery alone, numerous phase II and randomized trials
support the superiority of CRT over RT alone in terms of
locoregional control, but not survival. This topic is discussed in
detail elsewhere.

Although randomized trials have not
shown a survival benefit for either concomitant CRT or induction
chemotherapy followed by RT in patients with locoregionally
potentially resectable advanced laryngeal cancer (compared to
surgery with or without RT), there is a significant benefit in terms
of laryngectomy-free survival and locoregional control in favor of
concomitant CRT. This was demonstrated in the phase III United
States intergroup trial 91-11, in which 547 patients with stage III
or IV potentially resectable laryngeal cancer were randomly assigned
to radiation alone, induction chemotherapy followed by radiation, or
concomitant chemoradiotherapy utilizing cisplatin
every three weeks plus RT .

The primary endpoint was laryngectomy-free
survival (LFS). In the initial report, with a median follow-up of
3.8 years, two year LFS rates significantly favored the concomitant
chemoradiotherapy group (88 versus 75 and 70 percent for neoadjuvant
chemotherapy and radiation alone, respectively), and rates of local
control were also significantly better in this group (80 versus 64
and 58 percent, respectively. There were no significant differences
when induction chemotherapy followed by radiation was compared to
radiation alone, and overall survival was nearly identical among all
three groups (two-year and five-year survival rates 74 to 76, and 54
to 56 percent, respectively).

In a later report presented at the
2006 meeting of the American Society of Clinical Oncology (ASCO),
there were no longer any differences in LFS between the groups
receiving concomitant chemoradiotherapy and induction chemotherapy
followed by radiation (47 versus 45 percent at 5 years,
respectively). However, the overall laryngeal preservation rate
still favored concomitant therapy (84 versus 71 percent
respectively, compared to 66 percent with radiation alone), as did
locoregional control rates.

Additional results of this trial are
described in detail elsewhere. Largely based upon these data,
concomitant chemoradiotherapy is preferred for patients with
locoregionally advanced laryngeal cancer.

Regimens testing induction
chemotherapy followed by concomitant chemoradiotherapy are under
investigation, and appear quite promising . At least three
randomized studies designed to determine whether the sequential
integration of induction chemotherapy followed by concurrent
chemoradiotherapy improves outcomes compared to concurrent
chemoradiotherapy alone are now in progress. Although none are
limited to laryngeal preservation, the implication of their results
for nonsurgical approaches to laryngeal and other head and neck
tumors are obvious.

Contraindications
There are no validated markers that consistently and reliably
predict outcome from organ-preserving therapy for patients with
locoregionally advanced laryngeal cancer. However, largely based
upon analyses of data from the VA laryngeal cancer study [71]
as well as uncontrolled prospective trials and retrospective
reports, patients with penetration of tumor through cartilage into
soft tissues are considered poor candidates for a larynx-preserving
approach . Primary surgery, usually a total laryngectomy, is
commonly recommended in this setting.

Management of the neck Patients with advanced primary
lesions should have elective treatment of the neck, even if
clinically N0. Treatment guidelines from ASCO recommend that
patients with clinically involved regional cervical lymph nodes (N1,
who are treated with definitive RT or chemoradiotherapy, and who
have a complete clinical response do not require elective neck
dissection. Neck dissection should be performed for patients who do
not have a complete clinical response to radiation therapy.

Surgical treatment of the neck is
recommended for all patients with N2 or N3 disease who are treated
with definitive RT or chemoradiotherapy, regardless of response .
The rationale for this recommendation includes the following

There is no standard imaging approach in this setting that
can reliably predict which patients harbor residual disease.

Salvage surgery for recurrent disease in the neck is rarely
successful of subsequently required in this setting.

Patients with clinically involved
cervical lymph nodes who are treated with surgery for the primary
lesion should undergo neck dissection. If there are poor risk
features, adjuvant concomitant chemoradiotherapy is indicated.

Summary
and ASCO guidelines Organ-sparing approaches, including
induction chemotherapy followed by RT, concomitant chemoradiotherapy
with or without induction chemotherapy, and, in some cases,
radiation alone, permit larynx preservation in patients with
locoregionally advanced laryngeal cancer, but none provides a
survival advantage over laryngectomy. Nevertheless, because of the
importance of the larynx to speech and swallowing function, all
patients with advanced cancer of the larynx or pyriform sinus should
be offered the option of organ preservation, unless contraindicated.

In keeping with this general
philosophy, clinical practice guidelines from ASCO recommend that
for patients with T3 or T4 laryngeal cancers without tumor invasion
through cartilage into soft tissue, larynx preservation is an
appropriate standard treatment approach In general, concomitant
chemoradiotherapy is preferred over induction chemotherapy followed
by RT.

POSTTREATMENT FOLLOW-UP The goal of posttreatment
surveillance is improved survival through early detection of
recurrent disease and identification of second primary cancers.
Principles of treatment for recurrent disease and second primary
HNCs is covered in detail elsewhere.

Continued cigarette smoking appears
to be associated with a worse outcome after RT. Patients should be
encouraged to abstain from smoking after diagnosis, throughout
treatment, and thereafter.

Patients with HNC are more likely to
develop second primary cancers than any other group of patients with
malignancy. This probably reflects the wide distribution of the
toxic effects of tobacco and alcohol, the major risk factors for HNC.

The late development of second
primary tumors is the most common cause of posttreatment "failure"
after 36 months. The major sites are head and neck, lung, and
esophagus. Patients with supraglottic laryngeal cancer are at a
particularly high risk of developing metachronous lung cancers

Despite the lack of defined survival
benefit from any posttreatment surveillance strategy, surveillance
protocols are in widespread clinical use after curative-intent
therapy for HNC. In general, the intensity of follow-up is greatest
in the first two to three years, which is the period of greatest
risk for disease recurrence.